Formulation for oral transmucosal administration of lipid-lowering drugs

ABSTRACT

The invention relates to a formulation for delivering by oral transmucosal administration at least one lipid-lowering active principle, preferably from the statin family, said formulation including said active principle in the base or salt form, an aqueous alcohol solution titrating at least 30° alcohol, and optionally a pH correcting agent and/or an antioxidant, said active principle being in a stable and completely dissolved state in the aqueous alcohol solution. The invention also relates to a method of preparing said formulation and to the use thereof, preferably in single-dose packaging, for treating and preventing hyperlipemia and/or cardiovascular conditions.

The present invention relates to a formulation for instantaneoussystemic administration by the oral transmucosal route of at least onelipid-lowering drug active principle, in particular an active principlebelonging to the statin family.

The invention also relates to a method of preparing this formulation andto its pharmaceutical use, in particular for treating hyperlipidemiaand/or for preventing and treating cardiovascular conditions.

The global pharmaceuticals market is dominated by products intended totreat or prevent cardiovascular conditions. A significant proportion ofthese products contain lipid-lowering drug molecules intended to treathyperlipidemia, including hypercholesterolemia.

Lipid-lowering drugs are pharmaceutically active principles capable oflowering the level of lipids in the blood and in particular ofinhibiting the production of cholesterol. The primary function of somelipid-lowering drugs is to reduce endogenous synthesis of cholesterol inthe liver by inhibiting the activity of HMG CoA reductase, a hepaticcell enzyme used in the synthesis of a cholesterol precursor, namelymevalonate.

There are various lipid-lowering drug active principles.

More particularly known are molecules from the statin family, notablyatorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, androsuvastatin.

Like all lipid-lowering drugs, statin molecules reduce the synthesis ofcholesterol by inhibiting the activity of HMG CoA reductase, but theyalso have potential capacity for reducing atheromatous plaque at thearterial endothelium, thus preventing or attenuating ischemic syndromes.Moreover, long-term treatment using statins prevents to a significantdegree the primary occurrence of myocardial infarctions and secondaryrelapse events after a first ischemic attack.

Also known are fibrates such as fenofibrate, emfibrozil, and ezetimibethat belong to another class. These molecules act mainly by reducing thedigestive absorption of cholesterol via the intestinal wall, anabsorption area known as “brush-border mucosa”. In contrast, they haveno effect on central hepatic synthesis of cholesterol and they thereforeremain accessory or accompanying treatments for treatment with statins,with which they are generally prescribed simultaneously, in certainhighly-specific cases.

Lipid-lowering drugs in general, and statins in particular, areconventionally administered orally.

Administration by intravenous injection has been experimented with, butalthough rapid and efficaceous, it is not suitable for basic dailytreatment of hypercholesterolemia or for preventing heart attacks.Administration by transfusion requires dedicated personnel and the useof special equipment. It is costly and too burdensome for patients, whoseek the simplest and most readily available ambulatory treatment.

The best-known oral form of administration is enteral administration viapills or capsules.

However, lipid-lowering drugs, notably statins, have physico-chemicaland pharmacological characteristics that make their systemicbioavailability and their activity problematic, some causing intoleranceproblems, mainly digestive and muscular problems, depending on the doseadministered orally.

This is caused for the most part by the lipophilic or ampiphilic natureof these low molecular weight molecules that, when introduced into thedigestive tract and the stomach, suffer from the so-called “digestivefirst pass” effect, i.e. deterioration and losses linked to the stomachenvironment or to variations in intestinal physiology. Stomach passagewith a very acid pH followed by passage through the duodenum and thesmall intestine furthermore produces known physico-chemical or enzymaticinterference that may denature and degrade the absorption of thelipid-lowering drug molecules. Once absorbed, the intact residualfraction of the administered dose of lipid-lowering drug reaches theportal vein via the mesenteric venous network to end up at the hepaticlobules and the structures known as the Disse space, where they aresubjected to a so-called “hepatic first pass” effect that causes theirmetabolisation and/or more or less intense deterioration, with theproduction of numerous metabolites, some of which are inactive or toxicand may contribute to side effects.

The real bioavailable dose of active principle is therefore low: only aresidual part of the administered quantity reaches the liver to inhibitthe activity of HMG CoA reductase and reduce endogenous synthesis ofcholesterol. The bioavailability of these active principles also variesfrom person to person, both in terms of absorption time and in terms ofabsorbed active principle ratio.

For example, average known residual bioavailabilities are:

-   -   for a 20 milligram (mg) or 40 mg dose of lovastatin or        Simvastatin, around 5% of the administered dose;    -   for a 20 mg or 40 mg dose of provastatin, around 17% of the        administered dose; and    -   for a 10 mg to 80 mg dose of atorvastatin, from 12% to 14% of        the administered dose.

What is more, the time before the appearance of a plasmatic peakfollowing taking them is relatively long, averaging one to two hours.Some statin molecules are dispersed in a very large volume in theorganism, linked to their lipophilic character, with the result that amajor part of the active principle is distributed in a large organ andtissue space, exceeding 600 liters (L) for atorvastatin. Thus it isclear that, given this intense volumetric dispersion mechanism, only aresidual fraction of the active principle is liable to exert itspharmacological activity at the level of the hepatic cells.

Thus major problems occur.

A first problem is administering a sufficient dose of lipid-loweringdrug to the patient, given the weight of the person and the dilution anddispersion of this active principle in the organism, so that enough ofthe only meaningfully active part that acts on the HMG CoA reductase isavailable to be efficaceous.

A second problem is the latency time caused by metabolization anddispersion in the organism before the lipid-lowering drug moleculebegins to act.

Another problem is the appearance of side effects and intolerance,mainly digestive and muscular intolerance, linked to certainmetabolization products of the molecules administered.

Enteral administration of lipid-lowering drugs, which is the only routeused at present, is therefore in no way satisfactory, and it isnecessary to provide a form of administration offering betterpharmacokinetic, pharmacological, and therapeutic efficiency.

Thus there remains a need for a galenic formulation that is simple touse, of relatively low cost, easily available, and relativelynon-invasive, enabling administration of an immediately bioavailablequantity of lipid-lowering drugs without the problems of absorption anddigestive metabolization, so as to be able to effect treatment orprevention quickly, efficaciously, continuously, and at an effect/doseratio the most suited to hypercholesterolemia and/or cardiovascularconditions.

To address this need, the present invention proposes a lipid-loweringdrug formulation making it possible to deliver to the organism directlyand without delay just the required efficacious dose withoutbioavailability problems, with a dose/effect ratio as close as possibleto the ideally appropriate fraction for the required pharmacologicalactivity. This is a very specific galenic formulation making it possibleto guarantee instantaneous transmucosal administration of at least onelipid-lowering drug and/or cardiovascular protection active principle,in particular an active principle from the statin family, comprising:

-   -   said lipid-lowering drug and/or cardiovascular protection active        principle;    -   an aqueous alcohol solution consisting of water and ethanol        titrating at least 30° alcohol, in which said active principle        is present in a stable and completely dissolved state; and    -   optionally, a pH corrector agent and/or an antioxidant.

The invention also proposes a method of preparing this formulation andits use for treating hypercholesterolemia and/or preventing and/ortreating a cardiovascular event.

The formulation of the invention advantageously makes it possible toobtain at the lowest possible dose the best lipid-lowering drug and/orcardiovascular prevention effect that can be obtained with alipid-lowering drug and/or cardiovascular protector active principle. Itallows instantaneous and complete oral transmucosal passage of atherapeutic preparation based on at least one lipid-lowering drugmolecule, notably a statin, by preventing salivary dilution andswallowing and thus inopportune passage through the digestive tract. Thestatins are delivered quasi-instantaneously and directly to the livervia the arterial circulation network, serving as HMG CoA reductaseinhibitors. They are distributed by a direct route and initially to thewhole of the macro-arterial and micro-arterial vascular network thatcarries them, where, before any organic and tissue dispersion of saidactive principle in the organism and tissues, they can exercise theirrole of a potential atheromatosis reducer in direct contact withparietal lesions of the network.

Other features and advantages emerge from the following description ofthe invention, which concentrates on statins in particular, without thisbeing limiting on the invention, but transposable to otherlipid-lowering drug and/or cardiovascular protector active principlessuch as fibrates, e.g. fenofibrate, gemfibrozil, or ezetimibe.

Thus a first aspect of the invention provides a formulation for oraltransmucosal administration of at least one lipid-lowering drug and/orcardiovascular protection active principle, in particular an activeprinciple from the statin family, comprising:

-   -   said lipid-lowering drug and/or cardiovascular protection active        principle in base form or in salt form;    -   an aqueous alcohol solution consisting of water and ethanol        titrating at least 30° alcohol, in which said active principle        is present in a stable and completely dissolved state; and    -   optionally, a pH corrector agent and/or an antioxidant.

The active principle is present in a stable and completely dissolvedstate in the aqueous alcohol solution, to enable rapid absorption ofsaid active principle via the mucosa of the oral cavity.

The formulation of the invention preferably consists of the activeprinciple(s), the aqueous alcohol solution consisting of water andethanol, and optionally a pH corrector agent and/or an antioxidant.

The expression “lipid-lowering drug and/or cardiovascular protectoractive principle” refers to:

-   -   lipid-lowering active principles, i.e. any molecule capable of        inhibiting HMG CoA reductase and acting against excess        cholesterol and/or triglycerides in the blood;    -   cardiovascular protection active principles, i.e. any molecule        capable of reducing cardiovascular risk, notably capable of        reducing the risk of heart attack, the thickness of arterial and        coronary atheromatous plaque, etc.;    -   active principles considered to have both lipid-lowering drug        and cardiovascular protector effects, i.e. which, apart from        their capacity to reduce hypercholesteremia significantly, are        also capable of reducing cardiovascular risk, for example        atorvastatin and pravastatin.

The pharmaco-therapeutic category to which a molecule belongs is thatassigned to it in its Marketing Authorization (or Notice of Compliance).

The expression “transmucosal route” refers to any passive passage of alipophilic or amphiphilic molecule through the mucosa of the tongue,under the tongue, of the gums, of the palate, of the cheek, or any othermucosa of the oral cavity.

The expression “stable and completely dissolved state” refers to asolution state rendering the active principle in the molecular andweakly ionized state in its solution medium, this solution statepreventing any possibility of inopportune recrystallization. This stableand completely dissolved state may be monitored immediately on use ofthe formulation of the invention evaluating the visual appearance of thesolution obtained (measurement of the degree of limpidity) and then atthe level of the filtration residues (appearance or non-appearance ofcrystals), and finally in the medium-term and long-term during stabilitytracking tests at varying temperatures and relative humidities.

The expression “aqueous alcohol solution titrating X degrees alcohol”refers to a solution presenting a degree of alcohol equal to X,corresponding to the ratio between the volume of pure (100°) alcoholcontained in the aqueous alcohol solution and the total volume of thatsolution. The degree of alcohol of the aqueous alcohol solution variesas a function of the degree of the alcohol used to form the solution andthe water/alcohol ratio of the solution. For example, for 100° alcoholand a water/alcohol ratio of 50/50, the aqueous alcohol solutiontitrates 50° alcohol.

The expression “pH corrector agent” refers to any acid or base agent notdegrading the physico-chemical characteristics of the activeprinciple(s).

The pH corrector agent is preferably chosen from carbonates andbicarbonates of sodium, monosodium or disodium phosphates,triethanolamine, sodium hydroxide (NaOH) and potassium hydroxide (KOH)and also hydrochloric, sulfuric, phosphoric, citric, malic, lactic,succinic, and/or butyric acid agents

The expression “antioxidant” refers to an agent that prevents the lossof one or more electrons by a molecule, sometimes accompanied by a lossof protons (H+). The antioxidant is preferably chosen from vitamins E,C.

The lipid-lowering drug and/or cardiovascular protector active principleis present in base form or in salt form.

When the active principle is present only in base form, the formulationof the invention preferably contains an acid pH corrector agent.

When the active principle is present only in salt form, for example insuccinate, hydrochloric, or sulfate form, the formulation of theinvention preferably contains a base pH corrector agent.

In a highly preferred embodiment, the active principle is present inbase form. The lipid-lowering drug molecules in base form, in particularstatins in base form, being of lower molecular weight than those in saltform, dissolve and stabilize more easily in the formulation of theinvention and are better suited to faster oral transmucosal passage.

The active principle may be chosen in particular from molecules of thestatin family, such as atorvastatin, pravastatin, simvastatin,lovastatin, fluvastatin or rosuvastatin. The active principle ispreferably base atorvastatin, base simvastatin, base lovastatin,mevastatin, or base pivastatin. It may equally consist of fibrates, forexample fenofibrate, gemfibrozil, or ezetimibe.

The formulation of the invention preferably takes the form of an aqueousalcohol solution containing from 30% to 90% by volume ethanol, and 10%to 70% by volume water. The formulation of the invention even morepreferably takes the form of an aqueous alcohol solution containing from40% to 85% by volume ethanol and 15% to 60% by volume water.

The aqueous alcohol solution has a variable degree of alcohol of atleast 30°, preferably 30° to 70°, even more preferably 40° to 70°, andideally 45° to 65°.

The aqueous alcohol solution is advantageously the only solvent used inthe formulation of the invention.

Furthermore, the alcohol in the aqueous alcohol solution serves not onlyas a diluent for molecules that are insoluble in water but also topromote faster transmucosal absorption, at a rate that increases as afunction of the degree of alcohol used. The degree of alcohol of theformulation must nevertheless not exceed 70° because a higher degreewould be incompatible with a pharmaceutical product for oral applicationbecause it could burn the mucosa. By way of illustration, thedissolution coefficient of a statin in ethanol makes it possible toobtain complete dissolution of said active principle as high as 2 mg ofstatins per 0.75 milliliter (mL) of approximately 50° ethanol. Thiscoefficient may be modulated as a function of the required alcohol dose,the degree of alcohol and the water/ethanol ratio used.

The pH of the formulation of the invention is preferably in the range5.0 to 9.0, more preferably in the range 5.5 to 7.5. These pH values arefavorable to optimum absorption of the solution.

The formulation of the invention enables the active principle to crossthe oral mucosa passively within a few seconds of administration. Thisvery fast absorption makes it possible to prevent stagnation of thesolution and the active principle in the oral atmosphere and theirinopportune mixing with saliva, which is liable to degrade them, andwhich would break the continuity and the stability of dissolution of theactive principle(s). This short delay also makes it possible to preventreflex swallowing of the solution and the active principle that itcontains.

The transmucosal passage of the active principle presented in thesolution state of the invention to the external epithelial membrane,consisting of phospho-lipid structures that absorb passively by electiveaffinity the lipophilic molecules present in the stable and completelydissolved state, is based on osmotic or pulling pressure toward theother side of said membrane, in which the concentration of dissolvedactive principle and the degree of the alcohol solution concerned bothparticipate. The activity and strength of the osmotic pressure increasewith the degree of alcohol that serves as absorption promoter. There istherefore a powerful two-fold osmotic effect that is produced both bythe high degree of the alcohol in the formulation and also by the highand highly localized concentration of the dissolved active principle incontact with the mucosa.

In particular with lipid-lowering drugs, in particular statins, anappropriate degree of alcohol is in the range 40° to 70°, preferably inthe range 45° to 65°. This makes it possible to obtain andsimultaneously adjust the best coefficient of dissolution andstabilization of the molecules and to promote transmucosal passage witha delay of 4 seconds (s) to 6 s.

One particularly suitable embodiment corresponds to 1.0 mL of aqueousalcohol solution with a degree of alcohol of approximately 50° or 65°for 1 mg or 4 mg of statins.

The mucosa of the mouth have a very dense, quasi-spongy array ofmicro-vessels, so that the molecules of the alcohol solvent and thedissolved active principle, which pass through the lipophilic pores ofthe epithelial membrane, are instantly captured by the sublingual veinsand those draining the oral mucosa and conveyed to the jugular veins,and from there to superior vena cava and the right-hand side of theheart. The lipid-lowering drug molecules are then sent from theleft-hand side of the heart into the systemic arterial vascular tract,which distributes them directly and without delay to the hepatic cells.The lipid-lowering drug molecules therefore reach the hepatocyte cellsin the same nutrient and oxygenating blood flow indispensable to theirmetabolic life. Furthermore the passage of the lipid-lowering drugactive principles in contact with the arterial endothelial tissuecontributes to the anti-atheromatous and anti-ischemic activity of someof them.

This phenomenon is accentuated by the presence of the alcohol, whichcauses vasodilation with a local increase in the micro-vascular flow ofthe mucosa in direct contact with the formulation. Because of thislocally high micro-circulation flow, there is never equilibrium oneither side of the epithelial membrane: the concentration at itsexternal surface, in the mouth, always remains very high, untilexhaustion of the mechanism for want of molecules to absorb.

Use of the galenic formulation of the invention makes it possible toadminister passively a dose of lipid-lowering drugs, and in particularof statins, that is absorbed immediately on deposition in contact withthe mucosa, to be distributed instantly by the vascular route, with nodelay for its pharmacological action, and without first suffering thedestructive effects of digestive and hepatic passage. The galenicformulation of the invention therefore enables immediate and completeabsorption by the tissue of the lipid-lowering drug molecules containedin the formulation, followed by their distribution in the centralcirculation of the organism, generating a rapid “flash” typepharmacological response.

For example, with a galenic formulation of the invention prepared from 2mg of a base statin dissolved in 1.0 mL of a 50° ethanol solution, theremay be administered passively and quasi-instantaneously a verysignificant dose of active principle that is conveyed directly by thearteries to the liver, to the very heart of the hepatic cells, where itexercises its HMG CoA reductase antagonist function. This 2 mg dose isat least equivalent to that obtained and recognized as bioavailable andtherefore effective for administration by the enteral route, i.e. atbest 5% to 20% of the dose usually administered, depending on thestatins concerned. With the formulation of the invention, thebioavailability of the dose delivered by oral transmucosaladministration is equivalent or very close to that obtained by the oralroute after digestive absorption and metabolization of high doses.

The aqueous alcohol solution of the invention, titrating at least 30°alcohol, also has the advantage of dissolving lipid-lowering drugmolecules, in particular statin molecules, although they are lipophilicor amphiphilic, which allows their spontaneous absorption via the oralmucosa, which are also lipophilic and selective, and protects thepharmaceutical formulation against microbiological contamination withouthaving to introduce antibiotic preservatives.

Thus the aqueous alcohol solution of the invention has a four-foldefficacy:

-   -   it serves as a solvent for the lipid-lowering drug active        principle, in particular one from the statin family, which are        lipophilic or amphiphilic molecules of low molecular weight,        maintaining it in a state of stable and perfect dissolution;    -   it activates transmucosal passage of this dissolved active        principle presented in the molecular state in this way at the        level of the lipophilic oral mucous membrane;    -   the degree of alcohol increases the rate of transmucosal        absorption in two ways, by osmotic effect and by causing reflex        micro-vascular vasodilation, which accelerates the local        micro-circulatory flow; and    -   it is its own stability agent, which avoids the use of        conventional additives.

The present invention advantageously offers very simple production andvery good galenic stability: the extremely simplified water/alcoholsolution guarantees dissolution of the active principle and makes itpossible to dispense with most of the excipients normally used forconventional pharmaceutical preparations, including preservatives.

Thus it makes it possible to reduce production costs and at the sametime to reduce the risks of intolerance and possible interaction betweenactive principle and excipients.

Another advantage is that there is a very short delay in thepharmacodynamic action of the galenic formation of the inventioncompared to the slow absorption of existing lipid-lowering drugmedications, which takes from one to two hours after administration bythe oral digestive route.

The quasi-instantaneous vascular delivery proposed by the invention isentirely suitable for treating hypolipemia and hypercholesterolemia andpreventing and/or treating cardiovascular conditions. It can make itpossible for a patient himself or herself to administer a productcorresponding by weight to just what is really bioavailable via the oralroute, equivalent to the efficacy of flash intravenous injection,without the drawbacks that render this type of administrationunacceptable and inconceivable for uninterrupted basic treatment of tensof millions of patients.

It is an administration route that is much better in terms of simplicityand of non-traumatic administration availability, and also in terms ofattractive unit and therapeutic costs compared to existinglipid-lowering drug administration methods.

The improvement in terms of dose/effect ratio is at least 70% to 95%.With the formulation of the invention, an at least 70% to 95% lower doseis used to obtain a therapeutic effect without delay. The lipid-loweringdrug modules administered encounter no significant obstacle to theirinstantaneous distribution via the arteries to the hepatic cells, whichthey reach in a few seconds, so that the basic dose administered isconsiderably reduced compared to the recognized bioavailable doseindispensable for exercising the required pharmacological activity oflipid-lowering drugs. This dose is of course dependant on the requiredeffect. It is preferably in the range 2 mg to 8 mg of active principlefor volumes of aqueous alcohol solution in the range 0.2 mL to 2 mL. Thedose is preferably in the range 2 mg to 4 mg for each 1.0 mL of aqueousalcohol solution.

Moreover, the oral mucosa having an extremely large total absorptionarea, demultiplied by its creased villous tissue character,administration of the formulation of the invention is free of all riskof untimely swallowing or misrouting. It enables extremely fasttransmucosal passage, which limits mixing with alcohol and swallowing ofthe administered active principle, with the advantage of notdestabilizing the mucosa with various elements or excipients, as is thecase with some existing formulations.

Moreover, the effects of the alcohol are insignificant. For example,0.75 mL of a 50° ethanol aqueous alcohol solution could only result in aalcohol blood level below 0.005 grams (g) per liter of blood, accordingto the official Widmark reference formula, i.e. one hundredth of thelegal tolerance in France, which is set at 0.5 g per liter of blood.Moreover, the initial pulmonary expulsion of the alcohol solution has toallow virtually complete elimination of the ethanol in the form of vaporextracted via the respiratory route and exhaled before the ethanol canbe distributed in the organism. The alcohol vector is thus eliminatedalmost completely via the respiratory parenchyma.

A second aspect of the invention relates to a method of preparing theformulation.

A particularly suitable method of producing the galenic formulation ofthe invention comprises the following steps:

-   -   mixing alcohol and purified water and introducing into this        mixture at least one lipid-lowering drug active principle, for        example at least one active principle from the statin family;    -   optionally introducing an antioxidant;    -   stirring the preparation until a homogeneous suspension is        obtained;    -   optionally and progressively introducing a pH corrector agent        until the required pH in the range 5.0 to 8.0 is obtained;    -   further stirring until complete dissolution of the active        principle;    -   adding water if, necessary to make up to the required volume;        and    -   filtering.

The ethanol used may be absolute ethanol. It is preferably 95° ethanol.

In a preferred implementation, the method comprises the following steps:

-   -   mixing ethanol and purified water and introducing into this        mixture a lipid-lowering drug, preferably one from the statin        family, in base or salt form;    -   optionally introducing an antioxidant;    -   stirring the preparation, preferably for 10 minutes (min) to 60        min, until a homogeneous suspension is obtained;    -   optionally and progressively introducing a pH corrector agent        until a required pH in the range 5.0 to 8.0 is obtained;    -   further stirring, preferably for 5 min to 30 min, until complete        dissolution of the active principle;    -   adding water if necessary to make up to the required volume; and    -   filtering.

In a first variant, the method of the invention comprises the followingsteps:

-   -   mixing ethanol and water and introducing into this mixture a        lipid-lowering drug active principle, preferably one from the        statin family, in base form;    -   optionally introducing an antioxidant;    -   stirring the preparation, preferably for 10 min to 60 min, until        a homogeneous suspension is obtained;    -   progressively introducing an acid pH corrector agent until a pH        in the range 5.0 to 7, preferably close to 6.0, is obtained;    -   further stirring, preferably for 5 min to 30 min, until complete        dissolution of the active principle;    -   adding water if necessary to make up to the required volume; and    -   filtering using a 5 μm filter and dispensing the preparation        into single-dose bottles.

In a second variant, the method of the invention comprises the followingsteps:

-   -   mixing ethanol and water and introducing into this mixture a        lipid-lowering drug active principle, preferably one from the        statin family, in salt form;    -   optionally introducing an antioxidant;    -   stirring the preparation, preferably for 10 min to 60 min, until        a homogeneous suspension is obtained;    -   progressively introducing a basic pH corrector agent until a pH        in the range 6.0 to 8.0, preferably close to 7.0, is obtained;    -   further stirring, preferably for 5 min to 30 min, until complete        dissolution of the active principle;    -   adding water if necessary to make up to the required volume; and    -   filtering using a 5 μm filter and dispensing the preparation        into single-dose bottles.

The present invention may be used for instantaneous systemictransmucosal administration at lower and useful doses of lipid-loweringdrugs and/or cardiovascular protectors, notably statins, for exampleatorvastatin, pravastatin, lovastatin or simvastatin.

The formulation of the present invention may in particular be used toproduce a medication for treating hyperlipemia and/or preventing and/ortreating heart conditions. Such a medication exhibits therapeuticactivity in a very short time and at administered doses very much lowerthan the conventional doses.

The invention is therefore aimed at the use of the formulation for theproduction of a medication intended for treating hyperlipemia via theoral transmucosal route and at use of the formulation for the productionof a medication for oral transmucosal administration to prevent and/ortreat cardiovascular conditions.

The very small liquid volume of the formulation of the invention is veryeasy to administer. A patient may easily place it in their mouth indirect contact with a precise but smaller area of mucosa of the mouth,across the gums, or under the tongue.

According to a final aspect of the invention the formulation requiresspecific industrial packaging in order to allow its safe, simple andergonomic use and to prevent the active principle from being degraded bycontact with air as well as loss of degrees of alcohol.

One particular implementation consists in using an opaque glass orflexible metal-plastic or plastic packaging, preferably of small size,filled in an inert atmosphere such as nitrogen, to protect the stabilityof the composition and impermeability to oxygen and to radiation. Theseforms of packaging guarantee dissolution and stability over time of thedissolved active principles in hydro-alcohol solution of the invention.

These forms of packaging preferably include a cannula allowing precisedeposition of the solution of the invention in contact with anappropriate area of the mucosa.

For comfortable use by the patient, for easy transportation, dedicatedsealed packages may preferably be used for packaging. Even morepreferably, the galenic form of the invention is packaged in single-dosepackages of 0.5 mL to 2 mL, able to provide an adequate dose of activeprinciple.

This packaging is advantageously easy to transport and allows easy useof the galenic formulation at any time of day.

Examples of formulations of statins of the invention may be mentioned,with a volume of 0.75 mL or 1.00 mL, using approximately 50° alcohol,particularly suited to producing effective cholesterol synthesisinhibiting action at the level of the hepatic system with a delay ofonly a few minutes:

FORMULATION 1 1 mg Atorvastatin, 1.0 mL of 50° Alcohol

-   -   base atorvastatin (active principle): 1.0 mg    -   95° ethanol (diluent and absorption promoter): 0.5 mL    -   purified water (diluent): qsp 1.0 mL

This first formulation example may be produced using the methoddescribed below for a batch of 1000 doses, i.e. 1.0 L.

Into a stainless steel tank introduce 0.5 L of 95% V/V ethanol and 0.5 Lof purified water.

Introduce into the aqueous alcohol solution 1 g of base atorvastatin.

Using a helical stirrer, stir the preparation for 20 min to 40 min untila homogeneous suspension is obtained.

Continue stirring until complete dissolution.

Filter the preparation using a 5 μm polypropylene or like filter anddispense the preparation into 1.2 mL single-dose bottles.

FORMULATION 2 5 mg Atorvastatin, 1.2 mL of 50° Alcohol

-   -   base atorvastatin (active principle): 5.0 mg    -   95° ethanol (diluent and absorption promoter): 0.6 mL    -   purified water (diluent): qsp 1.2 mL    -   hydrochloric acid (pH corrector): qsp pH 6.0

This second formulation example may be produced using the methoddescribed below for a batch of 1000 doses, i.e. 1.2 L.

Into a stainless steel tank introduce 0.6 L of 95% V/V ethanol and 0.25L of purified water.

Introduce into the aqueous alcohol solution 5 g of base atorvastatin.

Using a helical stirrer, stir the preparation for 20 min to 40 min untila homogeneous suspension is obtained.

Then introduce hydrochloric acid progressively until a pH close to 6 isobtained (plus or minus 1).

Continue stirring until complete dissolution.

Make up with purified water to obtain a solution of 1.2 L volume andstir the preparation for 10 min to 30 min to ensure its homogeneity.

Filter the preparation on a 5 μm polypropylene or like filter anddispense the preparation into 1.2 mL single-dose bottles.

FORMULATION 3 2 mg Lovastatin, 1.0 mL of 50° Alcohol

-   -   base lovastatin: 2.0 mg    -   95° ethanol: 0.5 mL    -   purified water: qsp 1 mL

This formulation example may be produced using the method describedbelow for a batch of 1000 doses, i.e. 1 L.

Into a stainless steel tank introduce 0.5 L of 95% V/V ethanol and 0.5 Lof purified water.

Introduce into the aqueous alcohol solution 2 g of base lovastatin.

Using a helical stirrer, stir the preparation for 20 min to 40 min untila homogeneous suspension and complete dissolution are obtained.

Filter the preparation on a 5 μm polypropylene or like filter anddispense the preparation into 1.0 mL single-dose bottles.

FORMULATION 4 4 mg Lovastatin, 1.0 mL of 65° Alcohol

-   -   base lovastatin (active principle): 4.0 mg    -   95° ethanol (diluent and absorption promoter): 0.65 mL    -   purified water (diluent): qsp 1.0 mL    -   HCl (pH corrector): qsp pH 7.0

This formulation example may be produced using the method describedbelow for a batch of 1000 doses, i.e. 1.0 L.

Into a stainless steel tank introduce 0.650 L of 95% V/V ethanol and0.350 L of purified water.

Introduce into the aqueous alcohol solution 4 g of base lovastatin.

Using a helical stirrer, stir the preparation for 20 min to 40 min untila homogeneous suspension is obtained.

Then introduce hydrochloric acid progressively until a pH close to 7 isobtained (plus or minus 1).

Continue stirring until complete dissolution.

Filter the preparation on a 5 μm polypropylene or like filter anddispense the preparation into 1.0 mL single-dose bottles.

FORMULATION 5 2 mg Simvastatin, 1.0 mL of 65° Alcohol

-   -   base simvastatin (active principle): 2.0 mg    -   95° ethanol (diluent and absorption promoter): 0.65 mL    -   purified water (diluent): qsp 1.0 mL    -   HCl (pH corrector): qsp pH 7.0    -   vitamin E TPGS (antioxidant): 0.2 mg

This formulation example may be produced using the method describedbelow for a batch of 1000 doses, i.e. 1.0 L.

Into a stainless steel tank introduce 0.650 L of 95% V/V ethanol and0.350 L of purified water.

Introduce into the aqueous alcohol solution 2 g of base simvastatin and0.2 mg of vitamin E TPGS.

Using a helical stirrer, stir the preparation for 20 min to 40 min untila homogeneous suspension is obtained.

Then introduce hydrochloric acid progressively until a pH close to 7.0is obtained (plus or minus 1).

Continue stirring until complete dissolution.

Filter the preparation on a 5 μm polypropylene or like filter anddispense the preparation into 1.0 mL single-dose bottles.

FORMULATION 6 4 mg Simvastatin, 1.2 mL of 65° Alcohol

-   -   base simvastatin (active principle): 4.0 mg    -   95° ethanol (diluent and absorption promoter): 0.80 mL    -   purified water (diluent): qsp 1.2 mL    -   HCl (pH corrector): qsp pH 7.0    -   vitamin E TPGS (antioxidant): 0.2 mg

This final formulation example may be produced using the methoddescribed below for a batch of 1000 doses, i.e. 1.2 L.

Into a stainless steel tank introduce 0.800 L of 95% V/V ethanol and0.200 L of purified water.

Introduce into the aqueous alcohol solution 4 g of base simvastatin and0.2 mg of vitamin E TPGS.

Using a helical stirrer, stir the preparation for 20 min to 40 min untila homogeneous suspension is obtained.

Then introduce hydrochloric acid progressively until a pH close to 7.0is obtained (plus or minus 1).

Continue stirring until complete dissolution.

Make up with purified water to obtain 1.2 L of solution and stir thepreparation for 10 min to 30 min to ensure its homogeneity.

Filter the preparation on a 5 μm polypropylene or like filter anddispense the preparation into 1.2 mL single-dose bottles.

Of course, the invention is obviously not limited to the examplesdescribed above, and on the contrary covers all variants, in particularwith regard to the nature of the lipid-lowering drugs.

1. A formulation for oral transmucosal administration of at least onelipid-lowering drug and/or cardiovascular protection active principle,comprising: said lipid-lowering drug and/or cardiovascular protectionactive principle; an aqueous alcohol solution comprising water andethanol titrating at least 30° alcohol, in which said active principleis present in a stable and completely dissolved state; and optionally, apH corrector agent and/or an antioxidant.
 2. A formulation according toclaim 1, characterized in that the pH corrector agent is chosen fromsodium carbonates and bicarbonates, monosodium or disodium phosphates,triethanolamine, sodium hydroxide, potassium hydroxide and/orhydrochloric, sulfuric, succinic, butyric, phosphoric, citric, malicand/or lactic acid agents.
 3. A formulation according to claim 1,characterized in that the antioxidant is chosen from vitamins E, C.
 4. Aformulation according to claim 1, characterized in that the activeprinciple is in base form and the pH corrector agent is an acid agent.5. A formulation according to claim 1, characterized in that the activeprinciple is in salt form and the pH corrector agent is a basic agent.6. A formulation according to claim 1, characterized in that it has a pHin the range 5.0 to 9.0.
 7. A formulation according to claim 6,characterized in that the pH is in the range 5.5 to 7.5.
 8. Aformulation according to claim 1, characterized in that the aqueousalcohol solution titrates 30° to 70° alcohol.
 9. A formulation accordingto claim 1, characterized in that the aqueous alcohol solution comprises30% to 90% by volume of alcohol and 10% to 70% by volume of water.
 10. Aformulation according to claim 1, characterized in that the activeprinciple is chosen from the statins.
 11. A formulation according toclaim 1, characterized in that the active principle is chosen fromfibrates or ezetimibe.
 12. A method of preparing a formulation accordingto claim 1, characterized in that it comprises the following steps:mixing alcohol and purified water and introducing into this mixture atleast one lipid-lowering drug active principle; optionally introducingan antioxidant; stirring the preparation until a homogeneous suspensionis obtained; optionally and progressively introducing a pH correctoragent until the required pH in the range 5.0 to 8.0 is obtained; furtherstirring until complete dissolution of the active principle; addingwater if necessary to make up to the required volume; and filtering. 13.A preparation method according to claim 12, characterized in that itcomprises the following steps: mixing ethanol and purified water andintroducing into this mixture at least one active principle from thestatin family, in base or salt form; optionally introducing anantioxidant; stirring the preparation, preferably for 10 min to 60 min,until a homogeneous suspension is obtained; optionally and progressivelyintroducing a pH corrector agent until the required pH in the range 5.0to 8.0 is obtained; further stirring, preferably for 5 min to 30 minuntil complete dissolution of the active principle; adding water ifnecessary to make up to the required volume; and filtering.
 14. Use ofthe formulation according to claim 1, for the production of a medicationfor oral transmucosal administration intended for treating hyperlipemia.15. Use of the formulation according to claim 1, for the production of amedication for oral transmucosal administration intended for preventingand/or treating cardiovascular conditions.